Do Anti‐Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability

Abstract

Bredts rule holds as pecial place in the realm of physical organic chemistry,b ut its application to natural products chemistry-the field in which the rule was originally formulated-is not well defined. Herein, the use of olefin strain (OS) energy as areadily calculated predictor of the stability of natural products containing abridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into "isolable", "observable", and "unstable" classes. OS calculations on natural products,u sing contemporary forcefield methods,u nequivocally predict all structurally verified bridgehead alkene natural products to be "isolable". Thus,w hen one assigns the structure of ap utative bridgehead alkene natural product, an OS in the "observable" or "unstable" ranges is ared flag for error.

Reassignments and Corroborations of Oxo‐Bridged Natural Products Directed by OSE and DU8+ NMR Computation

“…[21,23] Theh igh OSE of hugonianene A( 29,3 2.1 kcal mol À1 ) suggested the structure may have been misassigned. Thepredicted spectra of 29 did not match the reported NMR data (see the Supporting Information): calculated 13 Cc hemical shift values gave av ery poor match, rmsd(d C ) > 11 ppm. DU8 + combines computations of structure and NMR properties of organic molecules at al ighter level of DFT theory (i.e., to accelerate computations on relatively large organic molecules including triterpenes), and is implemented with the following components:( a) structure optimizations carried out with B3LYP/6-31G(d);(b) the isotropic magnetic shielding values computed with wB97xD/6-31G(d) and corrected; [4d] (c) Fermi contacts evaluated with B3LYP/DU8 and scaled with the help of NBO-based corrections, [4c] to obtain spin-spin coupling constants (SSCC).…”

“…[14] To adapt this protocol to oxo-bridged bicyclica lkenes (i.e., structures with an oxygen atom directly connected to the double bond within the bicyclicf ramework), fifteen bicyclic oxo-bridged alkenes were chosen as shown in Figure 2. Five structures (5,8,10,13,17)a re analogues of molecules contained in the original hydrocarbon calibration set. Themolecules span abroad range of OSEs (i.e., from À3.9 to 24.7 kcal mol À1 ).…”

“…DU8 + analysis revealed mismatches between the experimental and calculated NMR data for both Kikuchisc ompound 21 and the Cytisus monoterpene 28 (see the Supporting Information). Thep redicted 13 Cc hemical shifts were also in much better agreement with the experimental data, rmsd(d C ) = 1.37 ppm. However, closer agreement was observed if C7 was inverted to 7b (36).…”

“…[11] Schleyer [12] had previously classified bridgehead alkenes into three categories-isolable, observable,and unstable-which have different characteristic OSE ranges.O SEs are readily calculated with molecular mechanics forcefields (the exact OSE cutoff values demarcating isolable,observable,and unstable alkenes depends on the forcefield used) and we previously established that all extant bridgehead alkene NPs whose structures have been verified fall into the isolable category. [13] Furthermore,w ep roposed that several putative NP structures [e.g., those for rosacedrenoic acid (1)a nd piperkadsin C( 2)] were likely misassigned, as those alkenes fell into the unstable category ( Figure 1). This classification scheme performed remarkably well for NPs with all-carbon skeletons,b ut its transferability to heteroatom-containing polycyclicf rameworks was not tested.…”

A theoretical study for the regioselective Diels–Alder reaction of 5,6‐fulleroid with strained anti‐Bredt olefins

“…[6,[23][24][25] The intrinsic reactivity of anti-Bredt olefin of fulleroid was investigated by olefin strain energy (OSE), [17] defined as the energy difference between an olefin and its corresponding dihydrogenated alkane. [26,27] Because of the aromatic conjugation, OSE of fullerene was 12 kcal/mol smaller than that of nonconjugated reference olefin, 1,2,3,4,5,6-hexahydropentalene. Conversely, the anti-Bredt olefin of fulleroid was only 3 kcal/mol smaller energy than the reference.…”